1. Field of the Invention
The present invention relates to a method of reducing intraocular pressure in mammalian subjects, particularly humans for treating and/or diagnosing glaucoma.
2. Background of the Related Art
In the United States, glaucoma is the second leading cause of legal blindness overall and the first leading cause of blindness in African-Americans. Primary open-angle glaucoma (POAG) is the most common form of glaucoma, and is widely recognized to affect 1-2% of the US adult population.
Glaucoma as an ophthalmologic disorder is responsible for significant visual impairment. The disease is characterized by progressive neuropathy caused in part by the deleterious effects of an increased intraocular pressure (IOP) on the optic nerve. In normal individuals, IOP ranges from 10 to 21 mm Hg. In contrast, in most individuals suffering from glaucoma, IOP is generally above 22 mm Hg. Loss of vision can also result from IOP only slightly above or even within normal range in patients with “normal-tension glaucoma.”
Several different types of glaucoma exist, each having different a pathophysiology. Glaucoma may be either “primary” or “secondary.” Primary glaucoma results from anatomical and/or physiological disturbances in aqueous fluid dynamics. This category includes primary open glaucoma (POAG), which constitutes the large majority of all glaucoma in the US. Angle-closure glaucoma results from blockage of the anterior chamber angle by another ocular structure (usually the iris), restricting the outflow of aqueous, and comprises a minority of glaucoma cases, but requires immediate attention. Secondary glaucoma occurs as a result of ocular injury or preexisting disease. Congenital glaucoma or infantile glaucoma is sometimes considered a third category. All types of glaucoma are thought to produce visual loss through the final pathway of optic neuropathy.
Glaucoma is associated with both non-pharmacological and pharmacological factors. Non-pharmacological factors include age, race, family history, diabetes, and hypertension. Pharmacological factors include the use of corticosteroids, which are thought to induce glaucoma by increasing resistance to outflow through the trabecular meshwork (TM).
Current glaucoma therapies are focused on either reducing intraocular pressure, or otherwise producing a “neuro-protective” effect, primarily on retinal ganglion cells. The main categories of therapy are surgical and pharmacological.
Both laser and regular (incisional) surgical procedures are used. Laser trabeculoplasty (LTP or SLT) or filtering surgery is used to improve aqueous drainage to reduce IOP. Problems with current surgical therapy include bleeding, infection, hypotony, loss of vision, decreasing effect over time, inability to titrate effect, and unpredictability.
Medications are also used to treat glaucoma. These may be topical or systemic agents. Glaucoma agents generally work by decreasing aqueous production, increasing aqueous outflow (via the trabecular and/or uveoscleral pathways), or a combination of both.
Problems with glaucoma medications include hyperemia, pain, headache, blurred vision, cataracts, retinal detachment, blindness, decreasing effect, dry mouth and nose, palpitation, tachycardia, hypertension, asthma, and other serious systemic side effects, including death. None of the currently used drugs is fully satisfactory. Besides the local and systemic toxicity mentioned above, many drugs have serious deleterious interactions with other drugs, and most drugs exhibit tachyphylaxis, or a decreasing effect with time. Moreover, current pharmacologic therapy also is often unable to lower IOP sufficiently to a level that prevents further visual loss due to glaucoma.
Many patients are already on “maximally tolerated medical therapy” without arresting their progressive visual loss due to glaucoma. Other patients are not candidates for surgery, for various medical or sociological reasons. Clearly, new treatment modalities and agents are needed for glaucoma patients, especially for those for whom current therapies are unable to stop progression of their disease towards eventual blindness.
There are few published reports regarding a possible immunologic basis for glaucoma. The great majority of the current literature reports negative evidence for an immunologic basis for glaucoma.
For example, patients with “chronic simple glaucoma,” “low tension glaucoma,” and “ocular hypertension” have been shown not to have a significantly different level of immunoglobulins compared to normal adult controls. In addition, no relationship has been shown between immunoglobulin levels and the severity of glaucoma as measured by visual fields and optic disc changes. Antinuclear antibodies have similarly not been found to correlate with the severity of glaucoma. The vast majority of glaucoma patients do not have an associated immune-related disease.
Recently, with the introduction of the new therapeutic class of prostaglandins and prostamides in the treatment of glaucoma (e.g., latanoprost (Xalatan, (TM)), bimatoprost (Lumigan (TM)), ophthalmologists have become more cognizant of the complicated role that inflammatory agents and anti-inflammatory agents play in the pathology, pharmacopathology, and pathophysiology of glaucoma. However, this recognition of the importance of inflammatory pathway modulation in the treatment of glaucoma has not lead to a similar recognition that immunologic modulation may be used to treat glaucoma, which is the underlying rationale for the present invention.
Because current teaching is that there is not a strong immunologic basis or etiology in the vast majority of glaucomas, the investigation for immunologic therapy for glaucoma has been largely ignored. Schwartz and colleagues have conducted studies on optic nerve crush injuries indicating that there may be an immunologic mechanism in the final pathway of ganglion cell damage in glaucoma that may be amenable to “rescue” or “neuroprotection” via immune therapy. They have also suggested that immune therapy may be used to moderate or mediate ganglion cell damage due to crush injury or other types of trauma, which they suggest may be helpful in treating optic neuropathies. However, they view this mechanism as totally separate from “hypotensive therapy” and do not consider the possibility that a vaccine may be used to create an immunologic response to lower IOP to treat glaucoma.
Even if most glaucomas do not have a primarily immunologic etiology, it may be possible that many types of glaucoma and glaucomatous neuropathy may be partially mediated by immunologic factors. For example, an immune mechanism may contribute to glaucomatous optic nerve damage. The immunologic response in glaucoma may be mediated by auto antibodies, or by a sensitizing antigen triggering an immune response that damages retinal ganglion cells. Such immunologic factors may be involved in many types of glaucoma, especially in “normal-tension” glaucoma. The immune system may also be involved in glaucoma by modulating cellular apoptosis and by other mechanisms of immune surveillance.
There are several reports in the literature associating HIV and/or AIDS with glaucoma. However, most of these are case reports of glaucoma caused by HIV and/or AIDS. For example, bilateral choroidal effusions with angle-closure glaucoma has been associated with HIV. In addition, bilateral angle-closure glaucoma has been associated with both HIV and AIDS, and when present in conjunction with uveal effusion has been reported as a presenting sign of HIV infection. Secondary acute angle closure glaucoma has also been reported as a complication of AIDS. High IOP, or secondary glaucoma, in response to HIV infection or AIDS is due largely to a mechanical mechanism (i.e., angle closure) and is noted here only to highlight the “teaching away” that prevented earlier recognition of the possible use immunotherapy as a treatment for glaucoma (rather than a cause of glaucoma).
Several investigators have noted sub-normal IOP (i.e., below 10 mm Hg) in AIDS patients. At first, it was thought that this was due to ophthalmic opportunistic infections in AIDS patients, such as cytomegalovirus (CMV) or pneumocystis pneumoniae (PCP) retinitis causing inflammation that impaired trabecular outflow, resulting in increased IOP. Later, clinicians reported sub-normal IOP in HIV patients without AIDS or any eye infections. Such reports were never pursued, however, as such patients generally saw well and were asymptomatic in their relatively hypotonous state, and so did not require therapy.
The scientific basis for this invention, therefore, involves an important clinical association that has been dismissed until the present invention as irrelevant: namely, that: 1) the low IOP seen in some HIV patients without AIDS is a result of the HIV virus having an immunologic effect on aqueous production and/or outflow, causing a decrease in IOP, and 2) a similar IOP-lowering effect can be achieved in glaucoma patients by stimulating an analogous immunologic response without causing HIV, AIDS or other immunologic disease, and 3) this immune-mediated IOP-lowering effect may be useful in the diagnosis of glaucoma suspects and/or treatment of glaucoma patients.
It is instructive to postulate some candidate mechanisms for the immunologic treatment of glaucoma. These include, but are not limited to, cellular or humoral immune mechanisms, lymphocytes including but not limited to T cells directed against ganglion cells, peptides, intermediate glutamate regulators or effectors, other antigens and/or antibodies, protein-mediated immunoreactivity, and other immune factors, mediators, modulators, and mechanisms.